Insulin resistance develops from obesity and physical inactivity and is commonly accompanied by other cardiovascular risk factors such as hypertension and dyslipidemia. The common association of these disorders, termed the metabolic syndrome, usually preceeds the development of overt type II diabetes mellitus by several years. Importantly, each of the factors in the metabolic syndrome contribute independently to the risk of cardiovascular disease and death. Preliminary experiments in our laboratory have demonstrated that the metabolic syndrome significantly impairs coronary blood flow regulation at rest and during increases in myocardial oxygen consumption. However, the mechanisms responsible for this pathophysiologic effect are presently unknown. Therefore, the objective of the proposed investigation is to delineate the mechanisms by which the pre-diabetic metabolic syndrome of obesity, hypertension and insulin resistance leads to the impairment of coronary flow control. We propose that the metabolic syndrome leads to chronically elevated levels of angiotensin II, norepinephrine and endothelin-1 which, in turn, mediate numerous pathophysiological effects (adrenoceptor dysfunction, increased free radical formation, endothelial dysfunction, increased coronary vasoconstriction). This hypothesis will be tested in vivo (PI, Tune) and in isolated coronary microvessels (Co-I Kuo), in dogs with and without a high fat diet to induce the metabolic syndrome. Circulating levels of angiotensin II, catecholamines and endothelin-1 will be measured to determine the extent to which high fat feeding increases these vasoregulatory factors. Coronary dose response experiments to selective agonists (angiotensin II, alpha and beta adrenoceptors, endothelin-1, nitric oxide) will be conducted in vivo and in vitro, and coronary free radical production, nitric oxide release and coronary mRNA receptor expression will also be measured. Chronic receptor blockade studies are also iplanned. Our preliminary data reveal provocative new findings that support the proposed hypotheses. Taken together, the proposed studies stand to offer valuable new information and insight into the neurohumoral mechanisms of obesity-related cardiovascular disease. In addition, data obtained from these experiments could lead to the development of novel therapeutic strategies to treat what is now considered to be a national epidemic. [unreadable] [unreadable]